The ongoing monkeypox virus (MPXV) outbreak is the largest ever recorded outside of Africa. We isolated and sequenced a virus from the first clinical MPXV case diagnosed in France (May 2022). We ...report that tecovirimat (ST-246), a US Food and Drug Administration approved drug, is efficacious against this isolate in vitro at nanomolar concentrations, whereas cidofovir is only effective at micromolar concentrations. Our results support the use of tecovirimat in ongoing human clinical trials.
Vaccinia virus (VACV) was used as a surrogate of variola virus (VARV) (genus Orthopoxvirus), the causative agent of smallpox, to study Orthopoxvirus infection. VARV is principally transmitted between ...humans by aerosol droplets. Once inhaled, VARV first infects the respiratory tract where it could encounter surfactant components, such as soluble pattern recognition receptors. Surfactant protein D (SP-D), constitutively present in the lining fluids of the respiratory tract, plays important roles in innate host defense against virus infection. We investigated the role of SP-D in VACV infection and studied the A27 viral protein involvement in the interaction with SP-D. Interaction between SP-D and VACV caused viral inhibition in a lung cell model. Interaction of SP-D with VACV was mediated by the A27 viral protein. Binding required Ca2+ and interactions were blocked in the presence of excess of SP-D saccharide ligands. A27, which lacks glycosylation, directly interacted with SP-D. The interaction between SP-D and the viral particle was also observed using electron microscopy. Infection of mice lacking SP-D (SP-D-/-) resulted in increased mortality compared to SP-D+/+ mice. Altogether, our data show that SP-D participates in host defense against the vaccinia virus infection and that the interaction occurs with the viral surface protein A27.
Background information. Vaccinia virus (VACV) was used as a surrogate of variola virus (genus Orthopoxvirus), the causative agent of smallpox, to study orthopoxvirus infection. VACV infects cells via ...attachment and fusion of the viral membrane with the host cell membrane. Glycosphingolipids, expressed in multiple organs, are major components of lipid rafts and have been associated with the infectious route of several pathogens.
Results. We demonstrate that the VACV‐WR (VACV Western‐Reserve strain) displays no binding to Cer (ceramide) or to Gal‐Cer (galactosylceramide), but binds to a natural sulfated derivative of these molecules: the Sulf (sulfatide) 3′ sulfogalactosylceramide. The interaction between Sulf and VACV‐WR resulted in a time‐dependent inhibition of virus infection. Virus cell attachment was the crucial step inhibited by Sulf. Electron microscopy showed that SUVs (small unilamellar vesicles) enriched in Sulf bound to VACV particles. Both the A27 and L5 viral membrane proteins were shown to interact with Sulf, indicating that they could be the major viral ligands for Sulf. Soluble Sulf was successful in preventing mortality, but not morbidity, in a lethal mouse model infection with VACV‐WR.
Conclusions. Together the results suggest that Sulf could play a role as an alternate receptor for VACV‐WR and probably other Orthopoxviruses.
Human enteric adenovirus Ad41 is associated with children gastroenteritis. To infect gastrointestinal cells, the invading virus must be acid-stable and resistant to inactivation by bile salts and ...proteases. In addition, it has to cross the mucus barrier before it infects mucosa cells. We show that Ad41 infectivity is not diminished by acid exposure, a condition limiting the infectivity of the respiratory Ad. This feature can be attributed to a large extent to the global basic charge of enteric Ad virions and to the stability of Ad41 fiber, a viral protein mediating virus attachment. Upon exposure to pH shock, the respiratory Ad2 loses its ability to interact with lipids while enteric Ad41 still binds to the major phospholipids of gastric and intestine mucus. In addition, contrary to respiratory Ad, enteric Ad41 interacts with several sphingolipid components of plasma membranes. These results show that the molecular bases of the Ad41 enteric tropism stem from its particular physicochemical properties.
The cutaneous radiation syndrome is the clinical consequence of local high-dose irradiation. It is characterized by extensive inflammation, necrosis, and poor revascularization of the skin, resulting ...in muscle inflammation and fibrosis. Based on these physiopathological processes, subcutaneous injections of adipose-tissue-derived stem/stromal cells have shown favorable effects on skin-wound healing in a minipig model of cutaneous radiation syndrome, in which muscle fibrosis persisted. Since fibrosis is mainly due to the inflammatory processes that often affect underlying tissues as well, the beneficial effects of intramuscular injections of adipose-tissue-derived stem/stromal cells on tissue recovery were evaluated. The polarization of the inflammatory response of irradiated muscle in a minipig model of cutaneous radiation syndrome was determined after acute local irradiation with 50 Gy gamma rays in a preliminary study (six minipigs). Analysis of the main inflammatory cytokines of the inflammatory response M1 (IL-1-beta and IL-6) and M2 (IL-10 and TGF-beta) by western blotting and in situ hybridization, as well as analysis of CD80/CD206 M1/M2 macrophage-specific markers by immunohistochemistry on minipig muscle samples, was performed 76 d after irradiation. The treatment of irradiated muscles with autologous adipose-tissue-derived stem/stromal cells led to an increase in IL-10 and TGF-beta, being associated with an increase in CD68+/CD206+ cells in this area. This highlights a polarization of M2 in the inflammatory response and indicates that adipose-tissue-derived stem/stromal cells may direct the irradiated tissues' inflammatory response towards a proregenerative outcome.
Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same ...drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug.
In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve AUC 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17.
Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 50% assigned to the bevacizumab group and 203 50% to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 10% in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 41% vs 80 40%), and platelet count decrease (43 22% vs 61 30%). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related.
Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice.
Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.
Applications using alumina nanoparticles (Al2O3 NPs) have incredibly increased in different fields of activity. In defense and aerospace fields, solid composite propellants use leads to complex ...combustion aerosols emissions containing high concentrations of Al2O3 NPs and hydrogen chloride gas (HCl). To better characterize potential hazard resulting from exposure to these aerosols, this study assesses cytotoxic effects of mixtures containing both compounds on human pulmonary alveolar epithelial cells (A549 cell line) after 24 h exposures.
After all co-exposures cell viability was >80%. However co-exposures decrease normalized real-time cell index. Significant decreases of intracellular reduced glutathione pool were also observed after co-exposures to γ-10 nm or γ/δ-13 nm Al2O3 NPs and HCl. Co-incubations with γ/δ-13 nm or γ-500 nm Al2O3 particles and HCl induced significant DNA double-strand breaks increases. Moreover all co-exposures and HCl alone disrupted cell cycle (increased G1 phase cells). Transmission Electron Microscopy (TEM) observations revealed γ/δ-13 nm Al2O3NPs adsorption and internalization in cell cytoplasm only, suggesting indirect genotoxic effects.
According to our results Al2O3 particles/HCl mixtures can induce cytotoxic effects and Al2O3 size and crystallinity are two main parameters influencing cytotoxic mechanisms.
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•Alumina particles and hydrochloric acid mixtures induce cytotoxic effects on alveolar epithelial cells•Co-exposures potentiate DNA double-strand breaks compared to simple exposures•DNA double-strand breaks occurrence is mainly influenced by alumina particles according to their size and crystalline form
The lung would be the first organ targeted in case of the use of Variola virus (the causative agent of smallpox) as a bioweapon. Pulmonary surfactant composed of lipids (90%) and proteins (10%) is ...considered the major physiological barrier against airborne pathogens. The principle phospholipid components of lung surfactant were examined in an in vitro model to characterize their interactions with VACV, a surrogate for variola virus. One of them, Dipalmitoyl phosphatidylglycerol (DPPG), was recently shown to inhibit VACV cell infection.
The interactions of poxvirus particles from the Western Reserve strain (VACV-WR) and the Lister strain (VACV-List) with model membranes for pulmonary surfactant phospholipids, in particular DPPG, were studied by Electron Spin Resonance (ESR) and proton Nuclear Magnetic Resonance (1H-NMR). ESR experiments showed that DPPG exhibits specific interactions with both viruses, while NMR experiments allowed us to deduce its stoichiometry and to propose a model for the mechanism of interaction at the molecular level.
These results confirm the ability of DPPG to strongly bind to VACV and suggest that similar interactions occur with variola virus. Similar studies of the interactions between lipids and other airborne pathogens are warranted.
Microbiota is known to influence response to anticancer immunotherapy. We examined whether antibiotic usage could impact nivolumab efficacy in patients treated for non-small-cell lung cancer (NSCLC).
...Seventy-four patients with NSCLC were included in this retrospective study. They received nivolumab between 2015 and 2016 (3 mg/kg i.v. q2w). The association between RECIST response and antibiotic usage was determined using Chi-square and Cox proportional hazard model.
A total of 17, 21 and 36 patients experienced response, stable disease and progression disease under nivolumab. Only 15 (20.3%) patients were exposed to antibiotic medication in the 3 months before the first nivolumab injection or during treatment. We found a similar response rate for the two populations, without impact of antibiotic exposure (Chi-square test p=0.75). Moreover, we observed no impact of antibiotic medication on progression-free survival under nivolumab (log-rank test, p=0.72).
Microbiota modification induced by antibiotics does not appear to affect the efficacy of nivolumab in patients with NSCLC.
Chemotherapy with anti PD-1/PD-L1 antibodies has become the standard of care for patients with metastatic non-small cell lung cancer (mNSCLC). Using lung tumor models, where pemetrexed and cisplatin ...(PEM/CDDP) chemotherapy remains unable to synergize with immune checkpoint inhibitors (ICIs), we linked the failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, sensitizing it to ICIs. PEM/CDDP plus a MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA- and TLR9-dependent manner. TLR9 or autophagy/mitophagy inhibition abolishes the anti-tumor efficacy of PEM/CDDP plus MEKi/anti-PD-L1 therapy. In human NSCLCs, high OPTN, TLR9, and CXCL10 expression is associated with a better response to ICIs. Our results underline the role of TLR9- and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy.
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•MEK inhibition synergizes with chemotherapy to induce CD8+ T cell recruitment in TME•Active KRAS-MEK pathway negatively regulates optineurin-dependent mitophagy•TLR9-dependent mitochondrial DNA sensing during mitophagy induces CXCL10 expression•MEK inhibitor and chemotherapy combination synergizes with PD-L1 blockade
Limagne et al. show that simultaneous treatment by chemotherapy and MEK inhibitors promotes mitophagy and mitochondrial DNA recognition by TLR9. TLR9 signaling leads to CXCL10 expression in cancer cells and CD8+ T cell recruitment to tumors and improves efficacy of PD-L1 blockade.
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